KR20020043840A - Method for stabilization of drug and decrease of skin-stimulation in the skin absorption having effect of removing wrinkle and protection wrinkle formation - Google Patents

Abstract

PURPOSE: A method for increasing the stability of a drug by using a semi-permeable film as a supporter of a transdermal administration type preparation, packing the preparation with packing paper of a multilayer film and filling nitrogen is provided. Whereby, the transdermal absorption type pharmaceutical preparation can reduce irritation on the skin or discomfort. CONSTITUTION: The transdermal administration type preparation comprises a supporter, an adhesive layer containing a drug having a wrinkle preventing or removing effect and a release film to stabilize the drug and reduce skin irritation in a transdermal administration type preparation containing a retinoid-based drug, wherein a semi-permeable film is used as a supporter of the transdermal administration type preparation, the transdermal administration type preparation is packed with packing paper of a multilayer film and nitrogen is filled at the same time.

Description

Method for stabilization of drug and decrease of skin-stimulation in the skin absorption having effect of removing wrinkle and protection wrinkle formation}

The present invention relates to a transdermal dosage form containing a drug having the effect of preventing and removing wrinkles, and more particularly, a method for reducing skin irritation while stabilizing a drug, more specifically a support; An adhesive layer containing a drug having an effect of preventing or removing wrinkles; And a semi-permeable film as a support in the transdermal dosage form consisting of a release film, and packing the transdermal dosage form having the above-mentioned composition with a package of a multi-film which cannot pass light while simultaneously filling the drug with nitrogen. To stabilize and additionally reduce irritation to the skin.

Drugs most widely used to remove or prevent wrinkles are components of the retinoid family in nature, and specific examples thereof include retinol, retinoic acid, and retinal. They have been reported to inhibit the activity of collagenase or elastinase in vitro and to increase collagen I and collagen III in vivo (C. Orfanos et al . "Current use and future potential role of retinoids in dermatology "Drugs, vol. 53, No. 3, 1997, pp 358-388).

However, retinoid-based components are easily denatured by air, heat, moisture, etc., and lose their activity. Therefore, there is a disadvantage that the effect of the retinoid-based drug is generally deteriorated because it is easily denatured due to moisture and air in the formulation in the cosmetics containing a large amount of water. To this end, various studies have been conducted to stabilize the retinoid-based components. To minimize moisture content, it is made in the form of a solid powder or in the form of a percutaneous dosage patch preparation mixed with an adhesive substance to a specific area of the skin. Techniques for delivering intensively are known (US Pat. Nos. 5,785,978 and 5,968,533).

However, when the existing formulation is applied to the desired area, foreign matters are mixed, the formulation is buried outside, and after use, there is a problem of washing off, and even in the case of a patch form, the stability of the drug against air, heat, and moisture is poor. Not only was not fully secured, due to the use of a non-breathable film, the skin hydration occurs, there was a problem such as causing erythema, skin irritation and wrinkles, and causing discomfort due to decreased feeling.

Accordingly, the present inventors have studied a method capable of stabilizing a drug in an agent having an effect of preventing and removing wrinkles, particularly a transdermal dosage form, and at the same time, without irritation or discomfort during use. In the transdermal dosage form consisting of a pressure-sensitive adhesive layer and a release film containing a drug, a semi-permeable film is used as a support, and the transdermal dosage form having such a configuration is packaged in a multi-film wrapper through which light cannot pass while simultaneously The present invention has been accomplished by discovering that the above object can be achieved by filling with nitrogen.

Accordingly, an object of the present invention is to provide a method for stabilizing a drug in a transdermal dosage form containing a drug having the effect of preventing and removing wrinkles, and at the same time reducing irritation and discomfort to the skin.

1 shows the structure of a transdermal dosage matrix formulation according to the invention.

[Description of Drawing Symbol]

1-1: Semi-breathable nonwoven film.

1-2: A pressure-sensitive adhesive gel containing a pressure-sensitive adhesive, drugs and active substances.

1-3: release film treated with silicon.

In order to achieve the above object, the method according to the present invention comprises a support; An adhesive layer containing a drug having an effect of removing or preventing wrinkles; And a transdermal dosage form consisting of a release film, wherein a semi-permeable film is used as a support and nitrogen is filled in the transdermal dosage form having the above-described configuration in a multi-film wrapper through which light cannot pass. Characterized in that.

Hereinafter, the present invention will be described in detail.

Since the method of the present invention uses a semi-permeable film as a support for the transdermal dosage form, it can solve problems such as skin erythema, skin irritation and skin wrinkles caused by the use of a conventional non-breathable film, unpleasant feelings in use, and the like. At the same time, the transdermal dosage form is packaged in a multi-film wrapping paper that cannot pass light, and nitrogen is filled therein to solve the problem of lowering the stability of the drug due to the use of a semi-permeable film.

Transdermal dosage formulations in the present invention include a support; An adhesive layer containing a drug having an effect of removing or preventing wrinkles; And a release film (see FIG. 1).

Of these, a semi-permeable film is used as the support. For example, the elastic nonwoven fabric of 150-200 micrometers specification which laminated the polyester nonwoven fabric and the elasticity polyurethane film is used.

The pressure-sensitive adhesive layer contains a hydrophobic pressure-sensitive adhesive resin, a drug stabilizer, a skin absorption enhancer, a skin side effect alleviator and the like together with the drug.

The drug contained in the adhesive layer in the transdermal dosage form of the present invention is a drug for the prevention and removal of wrinkles, which promotes the synthesis of collagen by the mechanism of inhibiting the activity of collagenase or elastinase to prevent and remove wrinkles. Naturally existing retinoid-based drugs such as retinol, retinal, retinic acid and artificially modified retinol palmitate known to be known, the content of which depends on the titer of each component, but 3,000 IU for pure retinol To 30,000 I.U. are appropriate.

Hydrophobic pressure-sensitive adhesive resin contained in the pressure-sensitive adhesive layer is used to minimize the inflow of water into the formulation to prevent instability in the water-soluble substrate of the retinoid drug, for example acrylic pressure-sensitive adhesive, acrylic-vinylacetate copolymer polymer There is an adhesive, a silicone pressure sensitive adhesive, a polyisobutylene pressure sensitive adhesive, and the amount of use thereof is controlled according to the inherent adhesion ability of each pressure sensitive adhesive, but in the case of an acrylic-vinylacetate copolymerized polymer adhesive, 60 to 90 weight based on the total weight of the adhesive layer. It is suitable to use in amount of about%.

Meanwhile, to stabilize the drug, antioxidants such as tocopherol, coenzyme Q10 (hereinafter referred to as CoQ10), ascorbic acid, kojic acid, arbutin, butylhydroxytoluene (BHT) and derivatives of the above materials alone or mixed It can be used in an amount of about 0.1-5.0% by weight.

In addition, a small amount of basic substances such as monoethyleneamine and triethanolamine can be added to improve the stability of the drug by adjusting the pH of the system between 6 and 8. The amount of addition depends on the basicity of each additive and the amount of other additives. .

Skin absorption enhancers used to improve the skin absorption of drugs include lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, dimethyl sulfoxide (DMSO), dodecyl sulfoxide, mono (Or di) methylacetamide, N-hydroxyethyl lactide, higher fatty acid esters, salicylic acid, sorbitol, pyrrolidone derivatives, butylene glycol ethyl ether, dodecylpyrrolidone, urea, glycerin, squalene, squalane, acetylation Inulin, cetyllaurate, olive oil, castor oil, ethoxystearyl alcohol, liquid paraffin, waserine, L-menthol, camphor, glycerin fatty acid ester, fatty acid mono (or di) ethanolamide, ethylene glycol monoethyl ether, polyoxy Ethylene alkyl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers and propylene glycol mono (or di) alkyl esters; Capacity it is common that a maximum amount of skin irritation occur, depending on the material that is different, but no more than up to 10% by weight.

In addition, the pressure-sensitive adhesive layer of the transdermal dosage form of the present invention may further contain polyhydric fatty acids, unsaturated fatty acids, other waxes, and the like, for a soft feel.

As the release film, a paper or polyethylene terephthalate film coated with silicon or fluorine is used.

In particular, in the present invention, a non-breathable package filled with nitrogen is used to prevent contact of the retinoid drug with air and moisture, and in order to prevent denaturation of the drug by light, aluminum is laminated in a multi-film. By using the wrapping paper, it was possible to improve the stability of the drug, which is important for the characteristics of the cosmetic of the present invention.

Hereinafter, after briefly showing examples of the present invention, the structure and effects of the present invention will be described in more detail through comparative and test examples. However, these do not limit the technical scope of the present invention.

<Examples 1-3>

ingredient Example 1 (unit; weight%) (1) Retinol 10S 0.09 (2) lauric acid 2.96 (3) PEG1500 8.94 (4) Vitamin C 5.92 (5) ubiquidecarenone 1.44 (6) triethanolamine 0.09 (7) mango butter 9.84 (8) Acryl-vinylacetate polymer copolymer solution 70.72

After disperse | distributing the components (1)-(7) of the said Table 1 uniformly in hexane, the component (8) was mix | blended and it stirred for 1 hour or more. When the suspension was in a uniform state, the stirring was stopped and the mixture was applied to a silicon or fluorine-coated paper or polyethylene terephthalate film using an applicator with a uniform thickness of 10 to 300 μm, and then at room temperature for 1 hour. It left to stand above and the solvent was fully volatilized and removed. At this time, after drying at room temperature may be further dried for 10 minutes in a hot air dryer of 80 ℃. After confirming that the solvent was sufficiently dried, the film laminated the nonwoven fabric and the polyurethane was laminated to prepare a transdermal dosage patch formulation in the form of a matrix. Next, the patch formulation was placed in a multi-layer laminated film of aluminum, filled with an inert nitrogen gas, and thermally bonded.

Comparative Example 1

A transdermal dosage patch formulation was obtained in the same manner as in Example 1 except that a non-breathable film (polyethylene terephthalate (PET) film or polyethylene (PE) film) was used instead of the laminated film of the nonwoven fabric and polyurethane.

Comparative Example 2

The transdermal dosage patch formulation was prepared in the same manner as in Example 1 except that the nitrogen filled package was not obtained to obtain a transdermal dosage patch formulation.

Comparative Example 3

A non-breathable film was used in place of the laminated film of the nonwoven fabric and polyurethane, and was prepared in the same manner as in Example 1 except that nitrogen-packed packaging was not obtained, thereby obtaining a transdermal dosage patch formulation.

Test Example 1: Cumulative stimulation test

In order to confirm the effect of the semi-breathable film used in the present invention, the transdermal dosage form preparations of Example 1 and Comparative Example 1 were cut and attached to the inner skin of 19 healthy men and women with a size of 2x2 cm 2, and then attached to the 3M micropore tape. It was completely fixed using. The patch was performed for 23 hours, and after 1 hour of removal, visual inspection was performed to determine the sum of the individual scores (CI) by CI sum and the value divided by the total number of subjects as CI mean. The mean score is represented by the following equation, Mean score = CI sum × 100 / [(Total Number of Tests (12) × Number of Subjects (19) × Maximum Value (4)]] Each formulation was patched again after the test, and the test was carried out daily It was carried out 14 times.The results are shown in Table 2 below.

Example 1 Comparative Example 1 CI Sum 5 6 CI Mean 0.26 0.32 Mean score 0.55 0.66 CI: Cumulative Index ** Mean score: Value by general patch test calculation method

From the test results, it can be seen that the irritation to the skin of the semi-breathable film is smaller than that of the non-breathable film.

Test Example 2: Stability Test

The transdermal dosage forms of Example 1 and Comparative Examples 1 to 3 were left in a 45 ° C. thermostat, and then titered for each product using high pressure liquid chromatography. A 7: 3 mixed solution of methanol and distilled water was used and analyzed through C18 column. The results are shown in Table 3.

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 45 ° C, 30 days 57% 52% 1.8% 2%

From the above results, it can be seen that the formulations of Example 1 and Comparative Example 1, which are packed with nitrogen filling, are more stable than the other examples.

[Test Example 3: skin wrinkle improvement effect test]

The results requested by a clinical institution using the percutaneous dosage form preparations of Example 1 and Comparative Examples 1 to 3 are shown in Tables 4 and 5 below.

1. Test Institution: Institut d'Expertise Clinique (France)

2. Subjects: 30 women with wrinkles around the eyes (average age 49 years)

3. 3% (1/30) of the subjects used wrinkle patch

4. Test Method

-After washing in the evening, apply the test product patch at night every other day and remove it in the morning (apply 6 to 9 hours overnight).

5. Evaluation method

Skin replica: measures the number and area of wrinkles

Survey Assessment

6. Test result

6-1. effect

Wrinkle reduction Surface area reduction Length reduction Example 1 13% 23% 17% Comparative Example 1 6% 10% 7% Comparative Example 2 4% 9% 5% Comparative Example 3 0% 0% 0% 1) Skin wrinkle improvement effect by replica 2) Result used for 12 weeks

6-2. Survey Evaluation

Wrinkle improvement effect Moisturizing Improvement Lifting effect Elasticity improvement effect Example 1 73% (73) 80% (73) 84% (77) 80% (73) Comparative Example 1 30% 70% 45% 50% Comparative Example 2 10% 15% 20% 15% Comparative Example 3 0% 0% 0% 0% * Values are percentage of the total number of subjects who answered positively to the questionnaire on the patched area ** Figures in parentheses resulted from 6 weeks of use

As a result of the above clinical experiments, it can be seen that the skin wrinkle improvement effect is remarkable when the transdermal absorption preparation for cosmetics of the present invention is used.

As can be seen from the above examples and test examples, the transdermal absorption preparations containing the drug having the effect of preventing and removing wrinkles provided in the present invention can simultaneously reduce the irritation or discomfort to the skin while the drug is stabilized. .

Claims (2)

Support; An adhesive layer containing a drug having an effect of preventing or removing wrinkles; And a transdermal dosage patch formulation comprising a release film, wherein a semi-permeable film is used as a support, and the percutaneous dosage formulation of the above-described structure is packed with nitrogen while packing with a package of multiple films through which light cannot pass. A method of reducing skin irritation while stabilizing a drug in a transdermal dosage form containing a retinoid drug effective for preventing and removing wrinkles. The method of claim 1, wherein the semi-breathable film is a film obtained by laminating a polyester-based nonwoven fabric and a urethane film.